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  • 1
    ISSN: 1573-7373
    Keywords: malignant glioma ; chemotherapy ; anthracyclines ; KRN8602(MX2) ; phase II study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract KRN8602(MX2) is a newly developed morpholino-anthracycline that has been found to cross the blood–brain barrier and be distributed in brain tissue after intravenous administration and to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. In order to confirm these promising preclinical observations clinically, we performed a phase II trial of KRN8602 in patients with recurrent malignant glioma. The 44 patients enrolled received at least 2 cycles of KRN8602 35 mg/m2/day at 3–4 week intervals by intravenous bolus. Of the 44 patients, 37 could be evaluated for response, and 39 for toxicity. One patient with anaplastic astrocytoma had a complete response (1/37, 3%), and 2 patients with anaplastic astrocytoma and 1 with brain stem glioma had a partial response (3/37, 8%). The overall response rate was 11% (4/37). All patients who responded had received prior chemotherapy that included nitrosoureas. No response was observed in the patients with glioblastoma. Myelosuppression was moderately severe, with 72% of patients developing grade 3 or 4 leukopenia. Severe nausea/vomiting was observed in 31% of the patients. No severe cardiotoxicity was observed. The results indicate that KRN8602 has modest activity against recurrent malignant glioma with relatively severe, but manageable toxicity. It seems to be worthwhile to further assess the efficacy and toxicity of KRN8602 against malignant glioma, which is generally less sensitive to chemotherapy.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-7373
    Keywords: anaplastic glioma ; glioblastoma ; medulloblastoma ; primitive neuroectodermal tumor ; subarachnoid dissemination ; intrathecal chemotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The toxicity and therapeutic effect of the ventriculolumber perfussion of 3-[(4-amino-2-methyl-5-pyrimidinyl)methyl-1-1(2-chloroethyl)-1-nitrosourea hydrochloride (ACNU) against subarachnoid dissemination of gliomas were studied. Twenty-one patients (6 patients with anaplastic glioma, 7 with glioblastoma and 8 with medulloblastoma or PNET) received ventriculolumber perfusion of ACNU when they were diagnosed as having subarachnoid dissemination. The course of perfusion and cumulative dose of ACNU was 10 times and 95 mg on average, respectively. Most of the patients received systemic chemotherapy in combination with perfusion therapy and some patients with radiotherapy. Response rate was 17% and median survival time after the diagnosis of dissemination was 12 months for anaplastic gliomas, 29% and 12 months for glioblastoma, and 88% and over 25 months for medulloblastoma and PNET. The ventriculolumber perfusion of ACNU was performed for prophylactic purpose in 7 patients with high risk at the early postoperative period in combination with conventional adjuvant therapy. The course of perfusion and cumulative dose of ACNU was 2.3 times and 21 mg on average, respectively. One patient developed subarachnoid dissemination and died 22 months after surgery. Other 6 patients survived without dissemination on median over 29 months after surgery. Side effects encountered were headache in 4 patients, nausea and vomiting in 5, a convalsion in 2, right facial weakness in 1, fecal incontinence in 3 and meningitis in 2. They were all temporary except for facial weakness occurred in one patient. These data suggest that the ventriculolumber perfusion of ACNU is a safe and useful in the treatment and prophylaxis against the subarachnoid dissemination of gliomas.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1573-7373
    Keywords: malignant glioma ; chemotherapy ; anthracyclines ; KRN8602 (MX2) ; phase II study
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract KRN8602 (MX2) is a newly developed morpholino anthracycline that crosses the blood–brain barrier where it becomes distributed in brain tissue after intravenous administration. This morpholino anthracycline has been found to be effective against human glioma cells and the intracerebrally transplanted tumors in vivo. We performed a phase II trial using KRN8602 as a single agent in malignant glioma patients who had not received prior adjuvant therapy. The 13 patients (5 glioblastomas, 7 anaplastic astrocytomas and 1 malignant oligodendroglioma) enrolled received at least 1 cycle of KRN8602 at 35 mg/m2/day in 3–4 week intervals by intravenous bolus. Ten of these patients could be evaluated for response, and 13 for toxicity. Three patients (1 glioblastoma and 2 anaplastic astrocytomas) demonstrated a complete response (3/10, 30%). Concerning side effects, myelosuppression was moderately severe, with 30.7% of patients developing grade 3 leukopenia. Severe nausea/vomiting was observed in 69% of the patients, however, cardiotoxicity was not observed. The results indicate that KRN8602 demonstrated modest activity against malignant glioma with relatively severe, but manageable toxicity. Further assessment of the efficacy and toxicity of KRN86O2 against malignant glioma may be worthwhile.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1573-7373
    Keywords: meningeal gliomatosis ; methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-gluco-pyranoside ; ventriculolumbar perfusion ; toxicity ; pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Ventriculolumbar perfusion of methyl 6-[3-(2-chloroethyl)-3-nitrosoureido]-6-deoxy-alpha-D-glucopyranoside (MCNU), a water soluble nitrosourea with log P-0.71, may be efficacious in the treatment of subarachnoid dissemination of malignant glioma. We used 2 dogs to study the neurotoxicity and pharmacokinetics of MCNU. MCNU (1 mg), dissolved in 10 ml of artificial CSF, was administered via the right lateral ventricle during a period of 18 to 42 min and the CSF was drained by lumbar puncture. The perfusion was repeated once a week for 10 consecutive weeks. No neurological and systemic symptoms were noted after perfusion. Histological examination of the brain and spinal cord showed local denudation of the ependyma and local subependymal spongy degeneration and gliosis in the lateral ventricle into which MCNU was administered in one dog and local denudation of the ependyma in the other. When administration was over a period of 21 to 38 min, the MCNU concentration in the lumbar CSF peaked at 11.11 to 50.67 Μg/ml, in 28 to 78 min. The area under the drug concentration-time curve (AUC) was 1152 Μg×min/ml on average, significantly larger than that of ACNU. The elimination phase followed linear kinetics and the half-time was 41.1 min on average, significantly longer than that of ACNU. These findings suggest that ventriculolumbar perfusion of MCNU may be effective in the treatment of subarachnoid dissemination of malignant glioma notwithstanding some local histological changes.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1573-7373
    Keywords: glioma ; growth factor ; oncogene
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A human malignant glioma cell line, U-251 Mg, cultured under serum free conditions, was shown to produce a growth factor for BALB/c 3T3 cells (glioma-derived growth factor-1, GDGF-1). The biological activity of GDGF-1 resided in a heat- and acid-resistant protein with a molecular weight (MW) of 25 kDa estimated by gel permeation chromatography. GDGF-1 activity was neutralized by a goat anti-human platelet derived growth factor (PDGF) antibody, indicating that the two factors were immunologically related. Furthermore, U-251 Mg cells constitutively expressed c-sis mRNA. When U-251 Mg cells were stimulated with bacterial lipopolysaccharide, 2 novel growth factors (GDGF-2 and GDGF-3) were produced in addition to the PDGF-like substance. GDGF-2 was determined to be 〉100 kDa MW and was not neutralized by the goat anti-PDGF antiserum. The biological activity of GDGF-3 was also heat- and acid- resistant with an apparent 14 kDa MW This factor also did not show any common antigenicity with PDGF. GDGF-2 and GDGF-3 are currently under investigation and evidence as to their natures will be published elsewhere. Our findings with this glioma cell line provide further evidence that inappropriate expression of growth factor-related genes could play important autocrine role(s) in the processes leading to malignant transformation and/or uncontrolled proliferation and may provide a paracrine stimulus for such processes as glioma neovascularization.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1573-7373
    Keywords: glioblastoma ; adjuvant therapy ; randomized trial ; ACNU ; intra-arterial administration
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This prospective randomized trial was performed to compare the effectiveness of intra-arterial ACNU with intravenous ACNU in newly diagnosed patients with supratentorial glioblastoma. The primary end points were overall survival and progression-free survival. Within 3 weeks after surgery, patients were randomly assigned to receive either intravenous or intra-arterial ACNU (80 mg/m2) once every 6 weeks concomitant with radiotherapy. Intra-arterial ACNU was administered for the first 3 courses followed by intravenous administration. Eighty-four patients were enrolled onto this study and among them 82 patients who passed eligibility criteria were analyzed. Patients characteristics were not different significantly between 2 treatment arms. Median survival and progression-free survival time was 59 and 24 weeks, respectively for intra-arterial arm and 56 and 45 weeks, respectively for intravenous arm. There was no significant difference respectively between two treatment arms. Among the prognostic variables including age, Karnofsky performance status, extent of surgery and treatment arm, Cox's proportional hazards model showed that age was the only significant factor for both survival and progression-free survival (P=0.003 and 0.016, respectively). With regard to toxicity, there was no significant difference between two treatment arms. Leukoencephalopathy was not observed in intra-arterial arm. In conclusion, intra-arterial ACNU when administered by the method in this study does not increase the survival and progression-free survival of newly diagnosed patients with glioblastoma over that afforded by intravenous ACNU.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-7373
    Keywords: c-fos ; fluorocytometry ; glioma ; platelet-derived growth factor ; protein kinase C ; trapidil
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Trapidil is a PDGF antagonist that can inhibit the proliferation of the PDGF-producing glioma cells, U251MG. As the mechanism of growth-regulation by trapidil remains unclear, we studied its effect on the growth of U251MG cells. We performed a cell cycle analysis and examined the intracellular transduction pathway and oncogene expression in serum-stimulated glioma cells with or without trapidil. After the serum starvation for 3 days, glioma cell proliferation was stimulated by the addition of serum. Cell cycle analysis showed that cell cycle perturbations induced by trapidil included a decreased transition rate from G0-G1 to S phase, suggesting that some metabolic event is required for progress through the G0-G1 phase and that this event is sensitive to trapidil. Internal signal transduction mechanisms are central in the molecular control of cell growth. One such regulator is the protein kinase C(PKC) system and the c-fos gene is likely to be a direct target of intracellular signal transduction pathways. Therefore, we hypothesize that the intracellular PKC activity and c-fos expression of the trapidil-treated cells are suppressed. We posit that trapidil affects the intracellular signal transduction pathway PKC activity and c-fos expression in cells stimulated with serum containing growth factors.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1573-7403
    Keywords: pituitary ; McCune-Albright syndrome ; pathology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A 11-year-old boy presented with right temporal hemianopsia and was evaluated of a possible pituitary adenoma. At the age of six, he underwent surgery for facial deformities due to fibrous dysplasia. On admission, he had acromegalic features, was 170 cm tall, weighing 66 kg. The left side of his face was slightly deformed, and a café-au-lait spot was found on his right face. Endocrinologic examination revealed elevated basal level of serum GH (103.6 ng/ml, normal 〈3 ng/ml) and PRL (259.1 ng/ml, normal 〈30 ng/ml). Other endocrine functions were normal. CT showed hyperostosis of the right frontal, occipital, sphenoidal and maxillary bones. Magnetic resonance imaging (MRI) revealed a pituitary macroadenoma with intraadenomatous cyst. On the basis of physical, endocrinologic and neuroradiologic examination, our diagnosis was pituitary adenoma with McCune-Albright syndrome. Surgery was performed by subfrontal approach. By light microscopy, the pituitary tumor represented a typical acidophilic adenoma. Immunoreactivity for GH and PRL were evident in most of the adenoma cells. Double immunostaining for GH and PRL demonstrated the co-existence of the two hormones in a few adenoma cells. However the majority of cells expressed only one hormone. After surgery the right temporal hemianopsia improved. Postsurgical endocrinologic examination revealed reduction in basal serum GH and PRL levels. Administration of bromocriptine decreased blood PRL levels but it had a limited action on GH hypersecretion.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1573-2568
    Keywords: FACTOR XA INHIBITOR ; MONOCYTE CHEMOATTRACTANT PROTEIN-1 ; REPERFUSION INJURY
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Activated factor X (FXa) is a trypsinlike serineprotease involved in the cascade of blood coagulation.The monocyte chemoattractant protein-1 (MCP-1) may beimportant in the pathophysiology of liverischemia-reperfusion injury. We investigated the effects of aselective FXa inhibitor, DX-9065a, on MCP-1 expressionafter ischemia-reperfusion in the rat liver. Liverischemia was induced in rats by occluding the portalvein for 30 min. DX-9065a was injected intravenously5 min before vascular clamping. Serum concentrations ofMCP-1 were measured by enzyme-linked immunosorbentassay. The levels of MCP-1 mRNA in the liver after reperfusion were determined by northern blotanalysis. In vitro MCP-1 production by peritonealmacrophages in response to alpha-thrombin was examined.Serum concentrations of MCP-1 increased and peaked at 6 hr after reperfusion. However,pretreatment of animals with DX-9065a resulted insignificantly smaller increases in the serumconcentration of MCP-1 after reperfusion in adose-dependent manner. Pretreatment with DX-9065a significantly reduced MCP-1 mRNAlevels in the liver after ischemia-reperfusion. In vitroMCP-1 production by peritoneal macrophages was enhancedby alpha-thrombin. In addition, DX-9065a significantly reduced tissue factor mRNA levels in peripheralmonocytes after ischemiareperfusion, compared tountreated animals. In conclusion, a selective inhibitorof FXa, DX-9065a, limited MCP-1 production after ischemia-reperfusion of the ratliver.
    Type of Medium: Electronic Resource
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